GENE-41187; No. of pages: 4; 4C: Gene xxx (2016) xxx–xxx

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Gene

journal homepage: www.elsevier.com/locate/gene

Meeting report A witness seminar on the history of the Human Gene Mapping Workshops

Emma M. Jones

History of Modern Biomedicine Research Group, School of History, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom. article info of America with USA-based scientists (Conversations in Genetics,

Article history: 2016), and the National Human Genome Research Institute's staff inter- Received 25 September 2015 views in Bethesda (NHGRI, 2016). Received in revised form 16 February 2016 Similar to other high-quality oral history resources, the Witness Accepted 18 February 2016 Seminar publications are intended to interact with many other primary Available online xxxx source materials which researchers and interested publics may engage with; for example, the ‘Codebreakers: Makers of Modern Genetics’ ar- chival collections of geneticists and related organisations digitised by the Wellcome Library, London, in collaboration with other institutions 1. Introduction (Codebreakers, 2016). The Witness Seminar publications also stand alone as significant historical narratives of biomedicine in their own In June 2015 the transcript of a ‘Witness Seminar’ on the history of right. the Human Gene Mapping Workshops c.1973–c.1991 was published Each Witness Seminar meeting is facilitated by a chairman, the en- by the History of Modern Biomedicine Research Group (www. tire proceedings are recorded and transcribed, and then edited, with histmodbiomed.org/witsem/vol54). The publication came from a the addition of references, bibliographies and biographies, and pub- meeting held in March 2014 to which key, mostly UK-based scientists lished both in hard copy and as a freely available pdf. Several meetings contributed, two of whom had participated in the first Human Gene have already been held and published on genetics-related or genetics- Mapping Workshop in 1973, and many of whom had been involved in focused topics, including on haemophilia (Tansey & Christie, 1999); subsequent HGMW (Table 1). rhesus factor (Zallen et al., 2004); genetic testing (Christie & Tansey, Witness Seminars are meetings to which a group of people who 2003); clinical genetics (Harper et al., 2010); clinical cancer genetics have been involved in particular discoveries, debates or events are invit- (polyposis and familial colorectal cancer) (Jones & Tansey, 2013); and ed to share their reminiscences and memories of ‘what really happened, clinical molecular genetics (Jones & Tansey, 2014). All publications can the stories behind the published literature’ to quote Professor Tilli be downloaded from the Group's website at: www.histmodbiomed. Tansey who heads the Group, and who developed this approach org/article/wellcome-witnesses-volumes. (Jones & Tansey, 2015). Through the use of oral history in a group format, the Witness Sem- inar publications make a unique contribution to the international cor- 2. Meeting report pus of primary historical resources on twentieth century human/ medical/clinical genetics, with a focus on the life stories of UK-based ge- Held over half a day, the Witness Seminar on the HGMW included a neticists. The group format enables participants in the seminars to chal- range of scientists and clinicians, as listed below, with Professor Peter lenge, corroborate, and/or expand on the reminiscences of their peers. Harper acting as a Chairman/facilitator (Fig. 1): Although these Witness Seminar events and publications differ in Professor Bert Bakker – style and content from the more traditional one-to-one approach to (Technician in molecular genetics, 1977 1989/Head of the Laborato- – oral history, they also relate to the body of interviews conducted with ry for Diagnostic Genome Analysis, 1990 2015, Leiden University). scientists and clinicians by other individuals and institutions, such as: Professor Tim Bishop the Genetics and Medicine Historical Network of Cardiff University led (Assistant/Associate/Adjunct Professor at Department of Medical In- – by Professor Peter Harper (Genetics and Medicine Historical formatics, University of Utah, 1979 1997; Director of the Leeds Institute – Network's, 2016); ‘Conversations in Genetics’ by the Genetics Society of Cancer and Pathology, 2011 ). Professor Sir Walter Bodmer (Professor of Genetics, University of Oxford, 1970–1979; Director of Research/Director General, Imperial Cancer Research Fund, 1979–1996; Abbreviations: HGMW, Human Gene Mapping Workshops; MPI, mannose phosphate isomerase. Head of the Cancer and Immunogenetics Laboratory, Weatherall Insti- E-mail address: [email protected]. tute of Molecular Medicine, University of Oxford, 1996–2005).

http://dx.doi.org/10.1016/j.gene.2016.02.030 0378-1119/© 2016 The Author. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article as: Jones, E.M., A witness seminar on the history of the Human Gene Mapping Workshops, Gene (2016), http://dx.doi.org/ 10.1016/j.gene.2016.02.030 2 E.M. Jones / Gene xxx (2016) xxx–xxx

Table 1 Professor Sue Malcolm Locations and dates of the Human Gene Mapping Workshops. (Died 2015. Emerita Professor of Molecular Genetics, University Col- HGM1 1973 New Haven lege London, Institute of Child Health). HGM2 1974 Rotterdam Professor Michael Morgan HGM3 1975 Baltimore (Director of Research Partnerships and Ventures at the Wellcome HGM4 1977 Winnipeg Trust (WT)/Chief Executive of the Wellcome Trust Campus in Cam- HGM5 1979 Edinburgh HGM6 1981 Oslo bridge, retired from the WT in 2002). HGM7 1983 Los Angeles Professor Sue Povey HGM8 1985 Helsinki (Chair of the HUGO Human Gene Nomenclature Committee, HGM9 1987 Paris 1996–2007; Haldane Professor of Human Genetics, University College HGM9.5 1988 New Haven – HGM10 1989 New Haven London, 2000 2007). HGM10.5 1990 Oxford Professor Chris Rawlings HGM11 1991 London (Project Manager of bioinformatics for HGM10.5/11, Imperial Cancer Research Fund; Head of Department of Computational Systems Biology, Rothamsted Research, 2004–). Professor Ian Craig Professor Ellen Solomon (Demonstrator/Lecturer, Genetics Unit, 1970–1996/Professor in Ge- (Senior/Principal Scientist, Imperial Cancer Research Fund, netics (titular), 1996–1998, Department of Biochemistry, University of 1976–1995; Head of the Department of Molecular Genetics, Oxford; Head of Molecular Genetics 1998–2001/Professor of Molecular 1995–2009, Prince Philip Professor of Human Genetics, 2004–). Psychiatric Genetics, King's College, London, 2001 — retired as Emeritus Dr. Susan Wallace Professor 2015). (Director, Americas Office of the Human Genome Organisation; Lec- Professor Malcolm Ferguson-Smith turer, Population and Public Health Sciences, University of Leicester). (Burton Professor of Medical Genetics, Glasgow University, 1973–1987; Professor/Head of Pathology, Cambridge University, then Professor Sue Povey (Fig. 2) of the Galton Laboratory gave a historical Professor of Pathology at Cambridge's Department of Veterinary Medi- introduction to the seminar, reviewing that Laboratory's contributions cine, 1987–1998). to human gene mapping research from its 1930s work on haemophilia Professor Peter Harper and colour blindness, comparing it with research conducted elsewhere (Professor of Medical Genetics; University of Wales College of Med- on Drosophila mapping. Later in the seminar she further framed the his- icine, 1971–2004; convenor of the Genetics and Medicine Historical torical context for the breakthroughs brought by gene mapping thus: ‘In Network, Cardiff University). the 1970s, people, I anyway, didn't think we'd ever find a gene by where Professor Veronica van Heyningen it was. I think that you (Walter Bodmer) introduced that in 1980, the re- (Postdoctoral scientist, Medical Research Council's Human Genetics ality of it’ (Jones & Tansey, 2015). Professor Sir Walter Bodmer (Fig. 3) Unit, 1977–1992, then Head of the Cell and Molecular Genetics Section, outlined his own intellectual role in the field, while acknowledging 1992–2012). the input of many others, and pointed to the role of somatic cell genetics Professor Maj Hultén research in paving the path to human gene mapping, with personal ref- (Head of the Regional Genetics Service at East Birmingham/Heart- erence to his experience of working in Guido Pontecorvo's lab. On this lands Hospital, 1975–1997; Professor Emerita, Karolinska Institutet, trajectory, he also cited a particularly influential paper of the late Stockholm, 2012–). 1960s: ‘…I think the initial, the first real, experiment that showed

Fig. 1. Participants at the Witness Seminar on Human Gene Mapping Workshops. Photograph copyright: 'Wellcome Library, London'.

Please cite this article as: Jones, E.M., A witness seminar on the history of the Human Gene Mapping Workshops, Gene (2016), http://dx.doi.org/ 10.1016/j.gene.2016.02.030 E.M. Jones / Gene xxx (2016) xxx–xxx 3

nervously late at night at Yale and being introduced to a cocktail party … this very impressive, tall character, Frank Ruddle, came and said, “You have to talk first thing tomorrow morning”, which was not the best news’ (Jones & Tansey, 2015). Craig evidently survived his nerves, and recalled how the distinctive format for the Workshops emerged at that first event, and also some low-tech methods that were employed: ‘You could see John Edwards and Bette Robson going around and calcu- lating lod scores on the backs of envelopes…’ (Jones & Tansey, 2015). Originally from Sir Walter's laboratory, Professor Veronica van Heyningen (Fig. 4) attended HGM2 in Rotterdam as a post-doc, and also remembered being unnerved by the imposing Frank Ruddle – foun- der of Yale's Human Genetics Department and the convenor of HGM1 – when she disproved his assignment of mannose phosphate isomerase (MPI)tochromosome7:‘… we had assigned very firmly the mitochon- drial malate dehydrogenase to chromosome 7 and it didn't co-segregate with MPI (Craig et al., 1974). Then, later on, we put MPI on a different chromosome, on 15.’ (van Heyningen et al., 1975)(Jones & Tansey, 2015). The predominantly UK-based perspectives were broadened by Pro- Fig. 2. Professor Sue Povey. Photograph copyright: 'Wellcome Library, London'. fessor Bert Bakker from Leiden University (Fig. 5), who spoke of his own contributions and especially the importance of new techniques linkage mapping in hybrids was Weiss and Green, who used the hybrid emerging in the 1970s for analysing chromosomes, such as heterochro- technique but not with lymphocytes, and they investigated the chromo- matin staining, and the breakthrough of Y W Kan and A M Dozy's re- somal localization of the thymidine kinase marker that was ultimately search on restriction fragment length polymorphisms by the end of shown to be on chromosome 17. That was really the first case that that decade (Kan & Dozy, 1978). Despite improving techniques, Profes- you could associate a marker with something you'd selected for …’ sor Malcolm Ferguson-Smith conveyed the painstaking work that his (Jones & Tansey, 2015). lab undertook on locating globin genes at the end of that decade: ‘… Sir Walter's comments are illustrative of how he and other partici- we knew which chromosomes the globin genes were on from the solu- pants in the Witness Seminar filled in the historical ‘jigsaw’ of gene tion mapping …. However, their location on the chromosome was not mapping research by linking their direct contributions to those of known. But you (Professor Sue Malcolm) were able to show, doing other geneticists. those wretched silver grain counts, that beta globin mapped to the On the first Human Gene Mapping Workshop, Professor Ian Craig short arm of chromosome 11 and alpha globin to the short arm of chro- discussed his experience of representing Bodmer's laboratory at mosome 16’ (Jones & Tansey, 2015). HGM1 in Yale, 1973: ‘I have a strong recollection of arriving very The seminar's participants discussed the wealth of data that had begun to proliferate by the late 1970s in terms of gene linkage analysis, and the subsequent influence of computing in the next decade of the Workshops' proceedings and documentation. In particular, Professor Chris Rawlings relived his role in coordinating the ambitious computa- tional infrastructure for HGM10.5 at St John's College in Oxford in 1990, where the first version of the programme Genome Database was used: ‘…I often describe it a bit like running a rock concert, as you had to bring a team of roadies in to get all this stuff in place … there was a fair amount of blood, sweat and tears involved in this operation …’ (Jones & Tansey, 2015). Another novel insight into the gene mapping

Fig. 4. Professor Veronica van Heyningen. Photograph copyright: 'Wellcome Library, Fig. 3. Professor Sir Walter Bodmer. Photograph copyright: 'Wellcome Library, London'. London'.

Please cite this article as: Jones, E.M., A witness seminar on the history of the Human Gene Mapping Workshops, Gene (2016), http://dx.doi.org/ 10.1016/j.gene.2016.02.030 4 E.M. Jones / Gene xxx (2016) xxx–xxx

the plenary lecture on ‘recording the voices of modern genetics’ (You're all history now, 2015). Since then, the homepage for the Human Gene Mapping Workshops c.1973–c.1991 publication has had over 250 unique page views on our Group's website, and we look for- ward to attracting future readers and researchers to this little- documented facet of the history of human genetics.

Acknowledgements

Grateful thanks to Professor Tilli Tansey for her assistance with pre- paring this paper, and also to the participants in the Witness Seminar and the Chair, Professor Sir Peter Harper. This work is funded by a Strate- gic Award (097271) to Professor Tilli Tansey from the Wellcome Trust.

References

Christie, D.A., Tansey, E.M. (Eds.), 2003. Wellcome Witnesses to Twentieth Century Med- icine 17. Wellcome Trust Centre for the History of Medicine at UCL, London http:// histmodbiomed.org/witsem/vol17. Codebreakers, 2016. Makers of Modern Genetics', digitised archives. http:// Fig. 5. Professor Bert Bakker. Photograph copyright: 'Wellcome Library, London'. wellcomelibrary.org/collections/digital-collections/makers-of-modern-genetics/ digitised-archives/ (accessed 26 January). Conversations in Genetics, 2016. http://www.genestory.org (accessed 26 January). community concerned the sensitivities of nomenclature, when Profes- Craig, I.W., van Heyningen, V., Finnegan, D., et al., 1974. Analysis of the mitochondrial en- sor Sue Povey recalled her time as Chair of the HUGO Human Gene No- zymes citrate synthase (EC 4.1.3.7) and malate dehydrogenase (EC 1.1.1.37) in human–mouse somatic cell hybrids. Cytogenet. Cell Genet. 13, 76–78. menclature Committee: ‘… criticism is so characteristic of Genetics and Medicine Historical Network's, 2016. Interviews With Founders of Human nomenclature, it's always so controversial and people get so het up And Medical Genetics. https://genmedhist.eshg.org/8.0.html (accessed 26 January). about it. Their gene is like their baby and everyone always agrees that Harper, P.A., Reynolds, L.A. (Eds.), 2010. Wellcome Witnesses to Twentieth Century Med- icine 39. The Wellcome Trust Centre for the History of Medicine at UCL, London one gene should only have one name but they are sure it should be http://histmodbiomed.org/witsem/vol39. theirs’ (Jones & Tansey, 2015). Also on politics, Professor Michael Mor- Jones, E.M., Tansey, E.M. (Eds.), 2013. Clinical cancer genetics: polyposis and familial gan shared his experience of the rocky road towards funding the colorectal cancer c.1975–c.2010. Wellcome Witnesses to Contemporary Medicine 46. Queen Mary University of London, London http://histmodbiomed.org/witsem/ Human Genome Project (HGP) within the Wellcome Trust, and its deci- vol46. sion ‘… that as soon as two kilobases of human DNA sequence was ac- Jones, E.M., Tansey, E.M. (Eds.), 2014. Clinical molecular genetics in the UK c.1975–c.2000. cumulated it would be released immediately on the internet, the “no Wellcome Witnesses to Contemporary Medicine 48. Queen Mary, University of ” … London, London http://histmodbiomed.org/witsem/vol48. intellectual property position would be taken That's had as much Jones, E.M., Tansey, E.M. (Eds.), 2015. Wellcome Witnesses to Contemporary Medicine 54. of an impact outside of genomics as probably the human genome has Queen Mary University of London, London 3, 46, 13, 17, 24, 20-1, 44, 59, 66-7, 84 had within genomics’ (Jones & Tansey, 2015). Such candid behind- http://histmodbiomed.org/witsem/vol54. Kan, Y.W., Dozy, A.M., 1978. Polymorphism of DNA sequence adjacent to human β-globin the-scenes revelations about the twists and turns of research into structural gene: relationship to sickle mutation. Proc. Natl. Acad. Sci. 75, 5631–5635. human genetics during the late twentieth century are precisely the NHGRI, 2016. History of Genomics Program, Oral History Collection. http://www. stuff that our Witness Seminars are made of. genome.gov/27557501 (accessed 26 January). Tansey, E.M., Christie, D.A. (Eds.), 1999. Wellcome Witnesses to Twentieth Century Med- icine. The Wellcome Trust, London http://histmodbiomed.org/witsem/vol4. 3. Conclusions van Heyningen, V., Bobrow, M., Bodmer, W.F., et al., 1975. Assignment of the genes for human mitochondrial malate dehydrogenase to chromosome 7, for mannose phos- phate isomerase and pyruvate kinase to chromosome 15, and, probably, for human The Witness Seminar on Human Gene Mapping Workshops has cre- – fi esterase-D to chromosome 13 using man mouse hybrids. Cytogenet. Cell Genet. 14, ated a signi cant addition to our outputs on the recent history of clinical 353–357. and medical genetics. The resultant publication provides a unique re- ‘You're all history now: recording the voices of modern genetics’; talk by Professor Tilli source for academics and other researchers/readers who are interested Tansey, Queen Mary University of London, video available at http://histmodbiomed. org/blog/you%E2%80%99re-all-history-now-recording-voices-modern-genetics in progress towards the Human Genome Project, and current advances (accessed 10 September) 2015. in genomics. We launched our volume at the European Society of Zallen, D.T., Christie, D.A. (Eds.), 2004. The Rhesus factor and disease preventionWellcome Human Genetics satellite meeting, the 6th International Workshop on Witnesses to Twentieth Century Medicine. The Wellcome Trust Centre for the History of Medicine at UCL, London http://histmodbiomed.org/witsem/vol22. the History of Human Genetics, Glasgow, in June 2015, where we pre- sented a poster on the seminar, and at which Professor Tansey gave

Please cite this article as: Jones, E.M., A witness seminar on the history of the Human Gene Mapping Workshops, Gene (2016), http://dx.doi.org/ 10.1016/j.gene.2016.02.030